Porphyrias are a group of metabolic disorders that are characterized by abnormalities in the production of heme and result in the accumulation of heme precursors in the liver or in the bone marrow and blood cells. Porphyrias present with neuro-visceral symptoms, skin problems, or both. Acute porphyrias usually have nerve symptoms and episodic crises resulting in nausea, vomiting, abdominal pain and hypertension. Non-acute porphyrias seldom have acute attacks but rather cause skin problems after exposure to light as these molecules react with light. The prevalence of different porphyria types varies significantly. Porphyria cutanea tarda is the most common (1:10,000; not all cases are genetic), while some other types have a prevalence of 1:1,000,000 or even less.

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD),
autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number
of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar);
HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD).
The list of associated, gene specific phenotypes are generated from CGD
or Orphanet databases.

The Blueprint Genetics porphyria panel covers classical genes associated with porphyria. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Bioinformatics

The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary.
In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel).
Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above.
The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline,
integrating state-of-the art algorithms and industry-standard software solutions.
Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency,
validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity.
We have incorporated a number of reference population databases and mutation databases such as, but not limited, to
1000 Genomes Project, gnomAD,
ClinVar and HGMD
into our clinical interpretation software to make the process effective and efficient. For missense variants,
in silico variant prediction tools such as SIFT, PolyPhen,
MutationTaster are used to assist with variant classification.
Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis,
including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present.
This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market.
Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles.
At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the
clinical statement together by evaluating the identified variants in the context of the phenotypic information
provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable
for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions.
Our classifications follow the Blueprint Genetics Variant Classification Schemes
based on the ACMG guideline 2015.
Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report.
Our experience with tens of thousands of clinical cases analyzed at our laboratory allowed us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic
using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed:
1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and
3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics.
Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call.
Reported copy number variations with a size <10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at Blueprint Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information
(genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant).
In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease,
the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes.
We also provide links to the references used, congress abstracts and mutation databases to help our customers further evaluate the reported findings if desired.
The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are
considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family.
In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore,
in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counseling.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases.
Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds.
Our laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available.
If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement
to the original ordering health care provider at no additional cost.

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* Please be advised that we only accept specimen collection kit requests from medical professionals. If you are a patient or family member of a patient, please contact your provider to place a kit order on your behalf.

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